Table 4.

Summary of therapeutic effects of IC blockers in macaque model.

Reference	IC Blocker	Target	Objective	Treatment	Outcomes
Vijayakumar Velu [96]	Humanized mouse anti-human PD-1 Ab (clone EH12-1540)	PD-1	SIV251/SIVmac239-infected Indian rhesus macaques	Anti-PD-1 Ab (3 mg/kg) in early chronic phase and in late chronic phase on days 0, 3, 7, and 10	Increases SIV-specific CD8+ T cells with improved functionality. Increases proliferation of memory B cells and SIV envelope-specific antibodies. Reduces plasma viral load. Prolongs survival of SIV-infected RMs.
Adam C Finnefrock [107]	Anti-human PD-1 Ab (clone 1B8)	PD-1	SIVmac239-infected rhesus macaques	Therapeutic model: single infusion of anti-PD-1 Ab 1B8 (5 mg/kg) to chronic SIV-infected macaques before or during ART Prophylactic model: anti-PD-1 Ab 1B8 (5 mg/kg) to naive macaques immunized with an SIV-Gag adenovirus vector vaccine	Therapeutic model: Transiently increases viral load; PD-1 blockade during ART has no discernible effect on SIV Gag-specific CD8+ T cells and CD4 T cell counts. Prophylactic model: Enhances SIV Gag-specific CD8+ T responses.
Ravi Dyavar Shetty [97]	Mouse anti- human PD-1 Ab	PD-1	SIV-infected rhesus macaques	Anti-PD-1 Ab (3 mg/kg) at either 10 or 90 weeks after SIV infection on 0, 3, 7, and 10 days	Downregulates type I IFN responses. Enhances gut junction-associated gene expression and reduces microbial translocation. Enhances immunity to pathogenic gut bacteria. Prolongs survival of SIV-infected RMs.
Praveen K Amancha [99]	Recombinant macaque PD-1 fused to macaque Ig-Fc (rPD-1-Fc)	PD-1	SIVmac239-infected rhesus macaques	rPD-1-Fc (50 mg/kg) alone or in combination with ART during the early chronic phase	Enhances SIV-specific CD4+ and CD8+ T cell proliferation and function. Fails to alter plasma viremia. Induces a significant delay in viral load rebound after ART interruption.
Geetha H Mylvagana [98]	Primatized anti–PD-1 Ab (clone EH12- 2132/2133)	PD-1	Chronic SIVmac251-infected rhesus macaques	Stage I: anti-PD-1 Ab (3 mg/kg/dose, 5 doses) between 24 and 30 weeks after infection on days 0, 3, 7, 10, and 14. Stage II: RMs again treated with anti-PD-1 Ab (10 mg/kg/dose, three monthly, 3 doses) at 26–30 weeks following ART initiation	Improves SIV Gag-specific CD8+ T cell functions prior to ART. Reduces the viral reservoir after ART initiation. Enhances viral control after ART interruption.
Diego A Vargas- Inchaustegui [102]	B7-DC-Ig fusion protein	PD-1	Chronic SIVmac251- infected rhesus macaques	ART plus B7-DC-Ig (10 mg/kg, weekly, 11 weeks), then B7-DC-Ig alone for 12 weeks	Maintains lower viremia, favorable T cell/Treg repertoire, and lower SIV-specific responses.
Elena Bekerman [110]	Human/rhesus chimeric anti- PD-1 antibody	PD-1	ART SIVmac251-infected rhesus macaques	Anti-PD-1 chimeric Ab (10 mg/kg, every other week, four doses) with or without TLR7 agonist vesatolimod (0.15 mg/kg, every other week, 10 doses)	No change in viral rebound kinetics following ART interruption. No change in SIV reservoir size. No change in frequency and function of SIV-specific T cells.
Sheikh Abdul Rahman [108]	Primatized anti–PD-1 antibody (clone EH12)	PD-1	Chronical SIVmac239-infected rhesus macaques	Immunized with a CD40L plus TLR7 agonist–adjuvanted DNA/MVA SIV239 vaccine (DNA vaccine: 1 mg/333 µL, 600 µL/dose, at weeks 38 and 42 MVA vaccine: 1 mL/dose, at weeks 46 and 60) during ART. Received anti–PD-1 treatment on days 0, 3, 7, 10, and 14, starting 10 days before the initiation of ART (3 mg/kg) and on week 38–44 starting with the first DNA prime during ART (10 mg/kg, 3 doses, every 3 weeks)	Increases the frequency of cytolytic CD8+ T cells in the blood and LN. Enhanced cytolytic CD8+ T cells localization in germinal centers of B cell follicles. Reduces viral reservoirs in lymphoid tissue. Controls viral rebound upon ART discontinuation.
ChunxiuWu [109]	Anti-PD-1 antibody (GB226)	PD-1	ChronicallySIV-infected macaque	Anti-PD-1 antibody injection (20 mg/kg) every 2 weeks from 1 to 7 weeks and rAd5-SIVgpe (1011vp in 1 mL PBS) at weeks 0 and 4 post ART discontinuation; ART treatment begins at week 3 before the initial vaccination	Exacerbates viral rebound after ART interruption. Accelerates the reactivation of the latent reservoir and AIDS progression. Increased CD4 and CD8 T cell counts. Improve SIV-specific CD4+ and CD8+ T cell immune function.
Enxiang Pan [106]	Genolimzumab	PD-1	Chinese rhesus monkeys	Genolimzumab injection (20 mg/kg, every two weeks) at weeks −1, 1, 3, 5, and 7 and rAd5-SIVgpe (1011vp) injection at week 0 and 4; at week 42 after the initial vaccination, animals were challenged with repeated low-dose SIVmac239	Augments and sustains vaccine-induced SIV-specific CD8+ T cell responses. Confers better control of pathogenic SIVmac239 infection.
Ping Che [101]	Avelumab	PD-L1	ART SIVmac239-infected rhesus macaques	Avelumab (20 mg/kg, weekly, for 24 weeks) and rhIL-15 (10 µg/kg, daily, continuous infusion for 10 days, two cycles), then, ART was discontinued and avelumab treatment continued until completion of the 24-week treatment	Transiently increases proliferation of natural killer and CD8+ T cells. Expands CXCR3+PD-1−/low CD8+ T cell subset with ability to secrete cytokines. No change in plasma viremia after ART interruption.
Amanda L Gill [100]	Avelumab	PD-L1	ART SIVmac239-infected rhesus macaques	Avelumab (20 mg/kg, weekly) At week 24, all treatments were discontinued	Leads to a trend of transient viral control after discontinuation of treatment.
Anna Hryniewicz [103]	MDX-010	CTLA-4	ART SIVmac251-infected rhesus macaques	Administered MDX-010 (10 mg/kg/injection) after ART initiation at weeks 5 and 8.	No impact on viral rebound following ART suspension. No impact on CD4 T cell and CD8 T cell counts. Decreases viral RNA level in LNs. Increases effector function of SIV-specific CD4+ and CD8+ T cells.
Todd Bradley [105]	Ipilimumab	CTLA-4	Cynomolgus macaques	Immunized with recombinant CH505 HIV Env gp120 (100 µg every 4 weeks) and ipilimumab (10 mg/kg) during the immunization 1–3	Promotes germinal center activity. Enhances HIV-1 Env antibody responses.
Justin Harper [104]	Nivolumab Ipilimumab	PD-1 CTLA-4	SIVmac239-infected rhesus macaques	Weekly nivolumab and ipilimumab over four weeks during ART, then, ART was interrupted two weeks afterwards with a seven-month follow-up	Enhances T cell proliferation and response in LNs and PBMCs. Induces robust viral reactivation in plasma. Decreases total and intact SIV-DNA in CD4+ T cells during ART in LNs. No change in SIV-specific CD8+ T cell responses during ART. No control of viremia after ART interruption.